JP2014144922A

JP2014144922A - Ａｃａｔ２阻害活性を示すピリピロペンａ構造簡略型誘導体

Ａｃａｔ２阻害活性を示すピリピロペンａ構造簡略型誘導体 Download PDF

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Publication number: JP2014144922A
Authority: JP; Japan
Prior art keywords: compound; added; mmol; solution; etoac
Prior art date: 2013-01-28
Legal status : Pending

Application number

JP2013012868A

Other languages

English (en)

Japanese (ja)

Other versions

JP2014144922A5 (enExample

Inventor

Masaki Otawa

正樹大多和

Satoshi Omura

智大村

Toru Nagamitsu

亨長光

Hiroshi Koda

洋供田

Current Assignee

Kitasato Institute

Original Assignee

Kitasato Institute

Priority date

2013-01-28

Filing date

2013-01-28

Publication date

2014-08-14

2013-01-28 Application filed by Kitasato Institute filed Critical Kitasato Institute

2013-01-28 Priority to JP2013012868A priority Critical patent/JP2014144922A/ja

2014-08-14 Publication of JP2014144922A publication Critical patent/JP2014144922A/ja

2016-06-09 Publication of JP2014144922A5 publication Critical patent/JP2014144922A5/ja

Status Pending legal-status Critical Current

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230000002401 inhibitory effect Effects 0.000 title claims description 17
PMMQOFWSZRQWEV-RVTXXDJVSA-N pyripyropene A Chemical group O([C@]1(C)[C@@H](OC(C)=O)C[C@@H]2[C@]([C@H]1[C@@H](O)C=1C(=O)O3)(C)CC[C@@H]([C@@]2(C)COC(=O)C)OC(C)=O)C=1C=C3C1=CC=CN=C1 PMMQOFWSZRQWEV-RVTXXDJVSA-N 0.000 title description 15
PMMQOFWSZRQWEV-UHFFFAOYSA-N pyripyropene A Natural products CC(=O)OCC1(C)C(OC(C)=O)CCC(C2C(O)C=3C(=O)O4)(C)C1CC(OC(C)=O)C2(C)OC=3C=C4C1=CC=CN=C1 PMMQOFWSZRQWEV-UHFFFAOYSA-N 0.000 title description 12
150000001875 compounds Chemical class 0.000 claims abstract description 131
150000003839 salts Chemical class 0.000 claims abstract description 13
239000012453 solvate Substances 0.000 claims abstract description 13
150000004677 hydrates Chemical class 0.000 claims abstract description 4
101000642613 Homo sapiens Sterol O-acyltransferase 2 Proteins 0.000 claims description 29
101000837584 Homo sapiens Acetyl-CoA acetyltransferase, cytosolic Proteins 0.000 claims description 26
125000000217 alkyl group Chemical group 0.000 claims description 11
125000003118 aryl group Chemical group 0.000 claims description 11
125000003545 alkoxy group Chemical group 0.000 claims description 7
229910052739 hydrogen Inorganic materials 0.000 claims description 7
239000003112 inhibitor Substances 0.000 claims description 7
239000001257 hydrogen Substances 0.000 claims description 6
125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 5
239000008194 pharmaceutical composition Substances 0.000 claims description 5
125000000753 cycloalkyl group Chemical group 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
125000005129 aryl carbonyl group Chemical group 0.000 claims description 3
125000003107 substituted aryl group Chemical group 0.000 claims description 3
239000004480 active ingredient Substances 0.000 claims description 2
125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 2
125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 2
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
102100028704 Acetyl-CoA acetyltransferase, cytosolic Human genes 0.000 claims 2
238000011282 treatment Methods 0.000 abstract description 31
206010003210 Arteriosclerosis Diseases 0.000 abstract description 14
208000011775 arteriosclerosis disease Diseases 0.000 abstract description 14
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VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 122
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239000000243 solution Substances 0.000 description 96
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238000006243 chemical reaction Methods 0.000 description 86
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GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 50
101150065749 Churc1 gene Proteins 0.000 description 50
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VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
238000005160 1H NMR spectroscopy Methods 0.000 description 37
238000000034 method Methods 0.000 description 36
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102100036673 Sterol O-acyltransferase 2 Human genes 0.000 description 27
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 26
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238000003786 synthesis reaction Methods 0.000 description 25
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 24
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YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
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239000012299 nitrogen atmosphere Substances 0.000 description 24
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230000015572 biosynthetic process Effects 0.000 description 22
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ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
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238000012746 preparative thin layer chromatography Methods 0.000 description 12
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 11
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AAULYJOXZLVNBE-OHGOKNIBSA-N [(5as,6s,8s,9as,10r)-10-hydroxy-5a-methyl-1-oxo-8-propan-2-yl-3-pyridin-3-yl-6,7,8,9,9a,10-hexahydropyrano[4,3-b]chromen-6-yl] acetate Chemical compound O([C@]1(C)[C@@H](OC(C)=O)C[C@H](C[C@H]1[C@@H](O)C=1C(=O)O2)C(C)C)C=1C=C2C1=CC=CN=C1 AAULYJOXZLVNBE-OHGOKNIBSA-N 0.000 description 10
LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
WADSJYLPJPTMLN-UHFFFAOYSA-N 3-(cycloundecen-1-yl)-1,2-diazacycloundec-2-ene Chemical compound C1CCCCCCCCC=C1C1=NNCCCCCCCC1 WADSJYLPJPTMLN-UHFFFAOYSA-N 0.000 description 9
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
230000003197 catalytic effect Effects 0.000 description 9
238000010791 quenching Methods 0.000 description 9
239000000126 substance Substances 0.000 description 9
BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 9
125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 8
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
239000000047 product Substances 0.000 description 8
FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 7
229940126214 compound 3 Drugs 0.000 description 7
229940125898 compound 5 Drugs 0.000 description 7
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 7
238000010626 work up procedure Methods 0.000 description 7
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
229920002472 Starch Polymers 0.000 description 6
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238000007796 conventional method Methods 0.000 description 6
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ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 description 4
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FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
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MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 4
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